Review Article
Candida Infections, Causes, Targets, and Resistance
Mechanisms: Traditional and Alternative Antifungal Agents
Claudia Spampinato1,2 and Daro Leonardi3,4
1
Departamento de Qumica Biologica, Facultad de Ciencias Bioqumicas y Farmaceuticas, Universidad Nacional de Rosario (UNR),
Suipacha 531, 2000 Rosario, Argentina
2
Centro de Estudios Fotosinteticos y Bioqumicos (CEFOBI, UNR-CONICET), Suipacha 531, 2000 Rosario, Argentina
3
Departamento de Tecnologa Farmaceutica, Facultad de Ciencias Bioqumicas y Farmaceuticas, Universidad Nacional de Rosario
(UNR), Suipacha 531, 2000 Rosario, Argentina
4
Instituto de Qumica Rosario (IQUIR, UNR-CONICET), Suipacha 531, 2000 Rosario, Argentina
Correspondence should be addressed to Daro Leonardi; leonardi@iquir-conicet.gov.ar
Received 8 April 2013; Revised 6 June 2013; Accepted 6 June 2013
Academic Editor: Abdelwahab Omri
Copyright 2013 C. Spampinato and D. Leonardi. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
The genus Candida includes about 200 different species, but only a few species are human opportunistic pathogens and cause
infections when the host becomes debilitated or immunocompromised. Candida infections can be superficial or invasive. Superficial
infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs. However,
invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial
antifungal therapies. Here, we briefly review our current knowledge of pathogenic species of the genus Candida and yeast infection
causes and then focus on current antifungal drugs and resistance mechanisms. An overview of new therapeutic alternatives for the
treatment of Candida infections is also provided.
1. Introduction
Candida albicans is the most important fungal opportunistic
pathogen. It usually resides as a commensal in the gastrointestinal and genitourinary tracts and in the oral and
conjunctival flora [15]. However, it causes infection when
the host becomes debilitated or immunocompromised. These
infections can be superficial and affect the skin or mucous
membrane [6] or can invade the bloodstream and disseminate to internal organs. Risk factors for invasive candidiasis
include surgery (especially abdominal surgery), burns, longterm stay in an intensive care unit, and previous administration of broad-spectrum antibiotics and immunosuppressive
agents [710]. Advances in medical management as antineoplasic chemotherapy, organ transplantation, hemodialysis, parenteral nutrition, and central venous catheters also
contribute to fungal invasion and colonization [11]. Other
Candida species found in healthy individuals include Candida glabrata, Candida tropicalis, Candida parapsilosis, and
Echinocandins
Inhibitors of
-glucan synthesis
Nucleoside analogues
Inhibitors of
nucleic acid
synthesis
Cell wall
Plasma membrane
Griseofulvine
Inhibitor of
microtubule
synthesis
Nuclei
Mitosis
Endoplasmatic
reticulum
Azoles,
allylamines, and
thiocarbamates
Inhibitors of
ergosterol synthesis
Antifungal class
Cytosol
Polyenes
Binding ergosterol
Mode of action
Drugs
Azoles
Inhibitors of lanosterol
14--demethylase
Miconazole
Econazole
Clotrimazole
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Echinocandins
Inhibitors of
(1,3)--D-glucan synthase
Caspofungin
Micafungin
Anidulafungin
Polyenes
Binding ergosterol
Nystatin
Amphotericin B
Nucleoside analogues
Flucytosine
Allylamines
Inhibitors of squalene-epoxidase
Terbinafine
Amorolfine
Naftifine
Thiocarbamates
Inhibitors of squalene-epoxidase
Tolnaftate
Tolciclate
Antibiotic
Griseofulvin
Table 1: Administration routes and pharmacokinetic parameters of representative antifungal agents belonging to the major families of
compounds.
Drug family
Azoles
Drug
Adm.
routea
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Oral
Oral
Oral
Oral
Caspofungin
IV
Micafungin
IV
Anidulafungin
IV
Amphotericin B
IV
Flucytosine
Oral
Echinocandins
Polyenes
Nucleoside
analogues
Pharmacokinetic parameters
AUCc
Protein
Half time Elimination References
Oral bioavailability max b
g/mL
mgh/L binding (%)
(h)
(%)
Urine
>90
0.7
400.0
1012
2731
[35, 37]
Hepatic
>55
1.1
29.2
99.8
2164
[35, 37]
Renal
>90
4.6
20.3
60.0
6
[35, 37, 38]
Feces
>98
7.8
17.0
99.0
1535
[35, 39]
[20,
35, 40,
Urine
<5
9.512.1 93.5100.5
96.0
10.6
41]
[20, 35, 40,
Feces
<5
7.110.9 59.9111.3
99.8
1117
41]
[20,
35, 40,
Feces
<5
3.47.5 44.4104.5
84.0
18.125.6
41]
Feces
<5
1.52.1
1317
>95
6.850
[35, 42]
7689
80
62
36
Renal
[31, 35]
Adm. route indicates administration route; fluconazole, itraconazole, and voriconazole can be administered by both intravenous and oral routes; IV:
intravenous; b max : maximal concentration; c AUC: area under the curve.
both for topical use and for the treatment and prophylaxis
of invasive fungal infections [22]. In this regard, these agents
have the approval of the US Food and Drug Administration
(FDA) and the European Medicines Agency (EMEA) [23].
2.2. Echinocandins: Inhibitors of the Glucan Synthesis. Echinocandins (caspofungin, micafungin, and anidulafungin) are
lipopeptidic antifungal agents that inhibit the synthesis of
fungal wall by noncompetitive blockage of the (1,3)--Dglucan synthase (Figure 1). This enzyme inhibition leads to
the formation of fungal cell walls with impaired structural
integrity, which finally results in cell vulnerability to osmotic
lysis [24]. All three agents (caspofungin, micafungin, and
anidulafungin) exhibit concentration-dependent fungicidal
activity against most species of Candida [25, 26] and have
been approved by the regulatory agency FDA for the treatment of esophageal and invasive candidiasis, including candidemia [2729].
2.3. Polyenes: Binding Ergosterol. Polyenes such as nystatin
and amphotericin B (both isolated from Streptomyces spp.)
bind ergosterol and disrupt the major lipidic component of
the fungal cell membrane resulting in the production of aqueous pores (Figure 1). Consequently, the cellular permeability
is altered and leads to the leakage of cytosolic components
and, therefore, fungal death [30].
2.4. Nucleoside Analogues: Inhibitors of DNA/RNA Synthesis.
Flucytosine is a pyrimidine analogue. It is transported into
fungal cells by cytosine permeases. Then, it is deaminated to
5-fluorouracil and phosphorylated to 5-fluorodeoxyuridine
monophosphate. This fluorinated nucleotide inhibits
thymidylate synthase and thus interferes with DNA synthesis
(Figure 1, [31]). The 5-fluorodeoxyuridine monophosphate
Table 2: Resistance mechanisms of major systemic antifungal drugs. Antifungal resistance is based on different mechanisms, namely, (i)
reduced drug intracellular accumulation, (ii) decreased target affinity/processivity for the drug, and (iii) counteraction of the drug effect.
Antifungal
class
Azoles
Polyenes
Nucleoside
analogues
5
3.4. Flucytosine Resistance. Primary resistance to flucytosine
remains low (<2%). Secondary resistance relies on inactivation of different enzymes of the pyrimidine pathway (Table 2)
as described below.
(i) Reduced Drug Intracellular Accumulation. Uptake of the
drug is affected by point mutations in the FCY2 gene which
encodes the cytosine permease [46, 128].
(iii) Counteraction of the Drug Effect. Acquired resistance
to flucytosine also results from point mutations in the
FCY1 gene which encodes for the cytosine deaminase or
FUR1 gene which encodes for the uracil phosphoribosyl
transferase. These enzymes catalyze the conversion of 5fluorocytosine to 5-fluorouracil and 5-fluorouracil to 5fluorouridine monophosphate, respectively. The most frequently acquired resistance to flucytosine is based on point
mutations in the FUR1 gene. Several point mutations have
been described in C. albicans, C. glabrata, and C. lusitaniae
[46, 128, 131, 132].
The rapid development of antifungal resistance, the toxicity and the variability in available formulations of some
agents, and the increase in the frequency of non-albicans
Candida spp. infections support the need for more effective
and less toxic treatment strategies.
General
source
Specific source
Plants
Natural
products
Marine organisms
Endophytic fungi
Microorganisms of
terrestrial environment
Synthetic
agents
Organically synthesized or
derived compounds
(not polymeric materials)
Examples
[47, 48]
[49]
[50]
Lipopeptides; terpenoids
Echinocandins, enfumafungin
[50, 51]
Compounds based on
N,N-dimethylbiguanide
complexes
Derived compounds from
traditional antifungal structures
Synthetic derived peptides
Me
(N,N-dimethylbiguanide)2 (CH3 COO)2 nH2 O
where Me: Mn, Ni, Cu, and Zn
[52, 53]
[54, 55]
Lactoferrin-derived peptides
Micafungin sodium, anidulafungin,
caspofungin acetate, pneumocandin, and
enfumafungin derivatives
Polymers containing aromatic or heterocyclic
structures
Cationic conjugated polyelectrolytes
Polymers with quaternary nitrogen atoms
within the main chain.
Block copolymers containing quaternary
ammonium salt
Synthetic peptides, synthetic dendrimeric
peptides
Arylamide and phenylene ethynylene
backbone polymers
Polynorbornene derivatives
Polymethacrylate and polymethacrylamide
platforms containing hydrophobic and cationic
side chains
References
Polymeric materials
Chelates
2-[(5-methylisoxazol-3-yl)amino]-2-oxo-ethyl
methacrylate and ethyl methacrylate
Polymers loaded with antifungal Organic compounds
compounds
Inorganic compounds
Imidazole derivative polymers
[56]
[57, 58]
[59]
[58]
[60]
[61]
[62, 63]
[64]
[65]
[66, 67]
[68]
[69, 70]
[71]
[72]
[73]
[71]
[7476]
[7779]
7
organic drugs; that is, chlorhexidine has been incorporated
into polymeric microparticles and into polymeric hydrogels
to modulate the release of the drug [74, 75]. Another research
group loaded triclosan into polymeric nanoparticles [76].
Antimicrobial inorganic agents frequently incorporate metals
into polymers, such as silver. This metal exhibits much
higher toxicity to microorganisms than to mammalian cells.
Polymeric nanotubes [77] and nanofibers [78] with silver
nanoparticles have been prepared by chemical oxidation
polymerization of rhodanine. Other silver nanocomposites
have been reported in the literature based on different silverloaded nanoparticles such as silver-zirconium phosphate
nanoparticles [79] or silver zeolites [142]. Another example of
inorganic compound loaded into polymers is copper. Copper
particles are also known for their antimicrobial activity,
although they are relatively less studied than silver [143].
The mentioned agents have been tried in vitro against
Candida; however, many of them are not used in clinical
treatments; in this regard, there are three agents with actual
promise: E1210, albaconazole, and isavuconazole (Figure 2).
E1210 is a broad-spectrum antifungal agent with a novel
mechanism of action based on the inhibition of fungal glycosylphosphatidylinositol biosynthesis [144, 145]. The efficacy
of oral E1210 was evaluated in murine models of oropharyngeal and disseminated candidiasis [80].
Results indicate that E1210 significantly reduced the
number of viable Candida in the oral cavity in comparison to
that of the control treatment and prolonged survival of mice
infected with Candida spp. Therapeutic responses were dose
dependent [80]. Table 4 shows the major pharmacokinetic
parameters after administration of E1210 in mice. E1210 was
also highly effective in the treatment of disseminated candidiasis caused by azole-resistant C. albicans or C. tropicalis [80].
Currently, E1210 is in Phase II.
Albaconazole is a new oral triazole with broad-spectrum
antifungal activity, unique pharmacokinetics, and excellent
tolerability [146]. It has been demonstrated that this compound was highly effective in vitro against pathogenic yeasts
and also in animal models of systemic candidiasis [146].
Oral bioavailability was calculated to be 80% in rats and
100% in dogs [81]. Assays in healthy human volunteers
showed that albaconazole was rapidly absorbed and presented good pharmacokinetic parameters (Table 4). In fact,
the therapeutic efficacy of a single dose of albaconazole at
40 mg was more effective than 150 mg of fluconazole for the
treatment of acute vulvovaginal candidiasis [81]. Currently,
albaconazole is in Phase II. In addition, low toxicity was
observed when albaconazole was administered to animals
and human volunteers [82].
Finally, isavuconazole (the active metabolite of the
water-soluble prodrug isavuconazonium) is a novel secondgeneration water-soluble triazole with broad-spectrum antifungal activity, also against azole-resistant strains. Studies
carried out with neutropenic mice of disseminated C. tropicalis or C. krusei infections showed that the treatment
significantly reduced kidney burden in mice infected with C.
tropicalis and both kidney and brain burden in mice infected
with C. krusei [147]. This azole is currently under Phase III
trials in patients with systemic candidiasis. Both oral and
OH
CH3
N
N
O
N
O
N
NH2
Cl
F
(a)
(b)
HO
F
N
F
(c)
Figure 2: Chemical structures of three agents with actual promise: E1210 (a), albaconazole (b), and isavuconazole (c).
Table 4: Pharmacokinetic parameters of some lead drugs.
Drug
Available
Experimental organisms
forms
E1210
Oral/IVa Mice
Oral
bioavailability
(%)
57.5
Albaconazole
Oral
nrd
Isavuconazonium
Oral
Very high
Isavuconazole
IVa
nrd
Pharmacokinetic parameters
Protein
Half
References
max c
max b
binding
time Elimination
(g/mL)
(h)
(%)
(h)
nrd
0.11
0.5
High
2.2
[80]
580
Feces
98
3056
[81, 82]
(proportional 24
to dose)
1.03
Feces
(100 mg
0.751
98
5677
[8183]
dose)
1.45
Feces
(100 mg
1.35
98
76104
[8183]
dose)
IV: intravenous; b max : maximal concentration; c max : time to reach maximal plasma concentrations after oral administration; d nr: not reported.
5. Conclusions
Although the antifungal drugs used in clinical treatments
appear to be diverse and numerous, only few classes of antifungal agents are currently available in oral and intravenous
Acknowledgments
This paper was supported by grants from Agencia Nacional
de Promocion Cientfica y Tecnologica (ANPCyT) to Claudia
References
[1] B. E. Jackson, K. R. Wilhelmus, and B. M. Mitchell, Genetically
regulated filamentation contributes to Candida albicans virulence during corneal infection, Microbial Pathogenesis, vol. 42,
no. 2-3, pp. 8893, 2007.
[2] T. G. Wu, B. M. Mitchell, T. S. Carothers et al., Molecular
analysis of the pediatric ocular surface for fungi, Current Eye
Research, vol. 26, no. 1, pp. 3336, 2003.
[3] J. M. Achkar and B. C. Fries, Candida infections of the
genitourinary tract, Clinical Microbiology Reviews, vol. 23, no.
2, pp. 253273, 2010.
[4] A. Rosenbach, D. Dignard, J. V. Pierce, M. Whiteway, and C. A.
Kumamoto, Adaptations of Candida albicans for growth in the
mammalian intestinal tract, Eukaryotic Cell, vol. 9, no. 7, pp.
10751086, 2010.
[5] J. R. Naglik, D. L. Moyes, B. Wachtler, and B. Hube, Candida
albicans interactions with epithelial cells and mucosal immunity, Microbes and Infection, vol. 13, no. 12-13, pp. 963976, 2011.
[6] R. Lopez-Martnez, Candidosis, a new challenge, Clinics in
Dermatology, vol. 28, pp. 178184, 2010.
[7] D. P. Kontoyiannis, E. Mantadakis, and G. Samonis, Systemic
mycoses in the immunocompromised host: an update in antifungal therapy, Journal of Hospital Infection, vol. 53, no. 4, pp.
243258, 2003.
[8] T. E. Zaoutis, J. Argon, J. Chu, J. A. Berlin, T. J. Walsh, and
C. Feudtner, The epidemiology and attributable outcomes of
candidemia in adults and children hospitalized in the United
States: a propensity analysis, Clinical Infectious Diseases, vol. 41,
no. 9, pp. 12321239, 2005.
[9] E. R. M. Sydnor and T. M. Perl, Hospital epidemiology and
infection control in acute-care settings, Clinical Microbiology
Reviews, vol. 24, no. 1, pp. 141173, 2011.
[10] M. A. Pfaller and D. J. Diekema, Rare and emerging opportunistic fungal pathogens: concern for resistance beyond Candida albicans and Aspergillus fumigatus, Journal of Clinical
Microbiology, vol. 42, no. 10, pp. 44194431, 2004.
[11] M. Mikulska, V. del Bono, S. Ratto, and C. Viscoli, Occurrence,
presentation and treatment of candidemia, Expert Review of
Clinical Immunology, vol. 8, pp. 755765, 2012.
[12] D. M. MacCallum, Hosting infection: experimental models to
assay Candida virulence, International Journal of Microbiology,
vol. 2012, Article ID 363764, 12 pages, 2012.
[13] M. A. Pfaller and D. J. Diekema, Epidemiology of invasive
candidiasis: a persistent public health problem, Clinical Microbiology Reviews, vol. 20, no. 1, pp. 133163, 2007.
[14] M. H. Miceli, J. A. Daz, and S. A. Lee, Emerging opportunistic
yeast infections, The Lancet Infectious Diseases, vol. 11, no. 2, pp.
142151, 2011.
[15] H. Wisplinghoff, T. Bischoff, S. M. Tallent, H. Seifert, R. P. Wenzel, and M. B. Edmond, Nosocomial bloodstream infections
in US hospitals: analysis of 24,179 cases from a prospective
nationwide surveillance study, Clinical Infectious Diseases, vol.
39, pp. 309317, 2004.
9
[16] M.-F. Cheng, Y.-L. Yang, T.-J. Yao et al., Risk factors for
fatal candidemia caused by Candida albicans and non-albicans
Candida species, BMC Infectious Diseases, vol. 5, article 22,
2005.
[17] M. Morrell, V. J. Fraser, and M. H. Kollef, Delaying the empiric
treatment of Candida bloodstream infection until positive
blood culture results are obtained: a potential risk factor for
hospital mortality, Antimicrobial Agents and Chemotherapy,
vol. 49, no. 9, pp. 36403645, 2005.
[18] B. P. Mathew and M. Nath, Recent approaches to antifungal
therapy for invasive mycoses, ChemMedChem, vol. 4, no. 3, pp.
310323, 2009.
[19] M. K. Kathiravan, A. B. Salake, A. S. Chothe et al., The biology
and chemistry of antifungal agents: a review, Bioorganic &
Medicinal Chemistry, vol. 20, pp. 56785698, 2012.
[20] D. W. Denning and W. W. Hope, Therapy for fungal diseases:
opportunities and priorities, Trends in Microbiology, vol. 18, no.
5, pp. 195204, 2010.
[21] H. Hof, A new, broad-spectrum azole antifungal:
posaconazolemechanisms of action and resistance, spectrum
of activity, Mycoses, vol. 49, no. 1, pp. 26, 2006.
[22] R. Hay, Antifungal drugs, in European Handbook of Dermatological Treatments, A. Katsambas and T. Lotti, Eds., pp. 700710,
Springer, Berlin, Germany, 2003.
[23] J. F. Aparicio, M. V. Mendes, N. Anton, E. Recio, and J. F. Martn,
Polyene macrolide antiobiotic biosynthesis, Current Medicinal
Chemistry, vol. 11, no. 12, pp. 16451656, 2004.
[24] N. Grover, Echinocandins: a ray of hope in antifungal drug
therapy, Indian Journal of Pharmacology, vol. 42, no. 1, pp. 911,
2010.
[25] D. Cappelletty and K. Eiselstein-McKitrick, The echinocandins, Pharmacotherapy, vol. 27, no. 3, pp. 369388, 2007.
[26] J. A. Vazquez, Anidulafungin: a new echinocandin with a novel
profile, Clinical Therapeutics, vol. 27, no. 6, pp. 657673, 2005.
[27] L. Ostrosky-Zeichner, D. Kontoyiannis, J. Raffalli et al., International, open-label, noncomparative, clinical trial of micafungin alone and in combination for treatment of newly diagnosed
and refractory candidemia, European Journal of Clinical Microbiology and Infectious Diseases, vol. 24, no. 10, pp. 654661, 2005.
[28] N. de Wet, A. Llanos-Cuentas, J. Suleiman et al., A randomized, double-blind, parallel-group, dose-response study
of micafungin compared with fluconazole for the treatment
of esophageal candidiasis in HIV-positive patients, Clinical
Infectious Diseases, vol. 39, no. 6, pp. 842849, 2004.
[29] J. Mora-Duarte, R. Betts, C. Rotstein et al., Comparison of
caspofungin and amphotericin B for invasive candidiasis, The
New England Journal of Medicine, vol. 347, no. 25, pp. 2020
2029, 2002.
[30] D. Sanglard and F. C. Odds, Resistance of Candida species to
antifungal agents: molecular mechanisms and clinical consequences, The Lancet Infectious Diseases, vol. 2, no. 2, pp. 7385,
2002.
[31] A. Vermes, H.-J. Guchelaar, and J. Dankert, Flucytosine: a
review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions, Journal of Antimicrobial
Chemotherapy, vol. 46, no. 2, pp. 171179, 2000.
[32] J. Onishi, M. Meinz, J. Thompson et al., Discovery of novel
antifungal (1,3)--D-glucan synthase inhibitors, Antimicrobial
Agents and Chemotherapy, vol. 44, no. 2, pp. 368377, 2000.
[33] D. Sanglard, A. Coste, and S. Ferrari, Antifungal drug resistance
mechanisms in fungal pathogens from the perspective of
10
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[75] A. S. Kiremitci, A. C
iftci, M. Ozalp,
and M. Gumusderelioglu,
Novel chlorhexidine releasing system developed from thermosensitive vinyl ether-based hydrogels, Journal of Biomedical
Materials Research B, vol. 83, pp. 609614, 2007.
[76] H. Zhang, D. Wang, R. Butler et al., Formation and enhanced
biocidal activity of water-dispersable organic nanoparticles,
Nature Nanotechnology, vol. 3, no. 8, pp. 506511, 2008.
[77] H. Kong, J. Song, and J. Jang, One-step preparation of antimicrobial polyrhodanine nanotubes with silver nanoparticles,
Macromolecular Rapid Communications, vol. 30, no. 15, pp.
13501355, 2009.
[78] H. Kong and J. Jang, Synthesis and antimicrobial properties
of novel silver/polyrhodanine nanofibers, Biomacromolecules,
vol. 9, no. 10, pp. 26772681, 2008.
[79] Y.-Y. Duan, J. Jia, S.-H. Wang, W. Yan, L. Jin, and Z.-Y. Wang,
Preparation of antimicrobial poly(e-caprolactone) electrospun nanofibers containing silver-loaded zirconium phosphate
nanoparticles, Journal of Applied Polymer Science, vol. 106, no.
2, pp. 12081214, 2007.
[80] K. Hata, T. Horii, M. Miyazaki et al., Efficacy of oral E1210,
a new broad-spectrum antifungal with a novel mechanism
of action, in murine models of candidiasis, aspergillosis, and
fusariosis, Antimicrobial Agents and Chemotherapy, vol. 55, no.
10, pp. 45434551, 2011.
11
[81] A. C. Pasqualotto and D. W. Denning, New and emerging
treatments for fungal infections, The Journal of Antimicrobial
Chemotherapy, vol. 61, pp. i19i30, 2008.
[82] C. Girmenia, New generation azole antifungals in clinical
investigation, Expert Opinion on Investigational Drugs, vol. 18,
no. 9, pp. 12791295, 2009.
[83] A. Schmitt-Hoffmann, B. Roos, M. Heep et al., Singleascending-dose pharmacokinetics and safety of the novel
broad-spectrum antifungal triazole BAL4815 after intravenous
infusions (50, 100, and 200 milligrams) and oral administrations
(100, 200, and 400 milligrams) of its prodrug, BAL8557, in
healthy volunteers, Antimicrobial Agents and Chemotherapy,
vol. 50, no. 1, pp. 279285, 2006.
[84] J. F. G. M. Meis and P. E. Verweij, Current management of
fungal infections, Drugs, vol. 61, no. 1, pp. 1325, 2001.
[85] H. L. Hoffman, E. J. Ernst, and M. E. Klepser, Novel triazole
antifungal agents, Expert Opinion on Investigational Drugs, vol.
9, no. 3, pp. 593605, 2000.
[86] D. M. Livermore, The need for new antibiotics, Clinical
Microbiology and Infection, vol. 10, no. 4, pp. 19, 2004.
[87] S. W. Redding, W. R. Kirkpatrick, S. Saville et al., Multiple
patterns of resistance to fluconazole in Candida glabrata isolates
from a patient with oropharyngeal candidiasis receiving head
and neck radiation, Journal of Clinical Microbiology, vol. 41, no.
2, pp. 619622, 2003.
[88] D. J. Skiest, J. A. Vazquez, G. M. Anstead et al., Posaconazole for
the treatment of azole-refractory oropharyngeal and esophageal
candidiasis in subjects with HIV infection, Clinical Infectious
Diseases, vol. 44, no. 4, pp. 607614, 2007.
[89] M. Ribeiro, C. R. Paula, J. R. Perfect, and G. M. Cox, Phenotypic and genotypic evaluation of fluconazole resistance in
vaginal Candida strains isolated from HIV-infected women
from Brazil, Medical Mycology, vol. 43, no. 7, pp. 647650, 2005.
[90] J. A. Vazquez, G. Peng, J. O. Sabel et al., Evolution of antifungal
susceptibility among Candida species isolates recovered from
human immunodeficiency virus-infected women receiving fluconazole prophylaxis, Clinical Infectious Diseases, vol. 33, no. 7,
pp. 10691075, 2001.
[91] A. Safdar, F. van Rhee, J. P. Henslee-Downey, S. Singhal, and
J. Mehta, Candida glabrata and Candida krusei fungemia
after high-risk allogeneic marrow transplantation: no adverse
effect of low-dose fluconazole prophylaxis on incidence and
outcome, Bone Marrow Transplantation, vol. 28, no. 9, pp. 873
878, 2001.
[92] M. Cuenca-Estrella, A. Gomez-Lopez, E. Mellado, M. J.
Buitrago, A. Monzon, and J. L. Rodriguez-Tudela, Head-tohead comparison of the activities of currently available antifungal agents against 3,378 Spanish clinical isolates of yeasts and
filamentous fungi, Antimicrobial Agents and Chemotherapy,
vol. 50, no. 3, pp. 917921, 2006.
[93] M. A. Pfaller, S. A. Messer, L. Boyken et al., Use of fluconazole
as a surrogate marker to predict susceptibility and resistance
to voriconazole among 13,338 clinical isolates of Candida
spp. tested by clinical and laboratory standards instituterecommended broth microdilution methods, Journal of Clinical Microbiology, vol. 45, no. 1, pp. 7075, 2007.
[94] M. A. Pfaller, S. A. Messer, L. Boyken et al., Cross-resistance
between fluconazole and ravuconazole and the use of fluconazole as a surrogate marker to predict susceptibility and
resistance to ravuconazole among 12,796 clinical isolates of
Candida spp, Journal of Clinical Microbiology, vol. 42, no. 7, pp.
31373141, 2004.
12
[95] T. Noel, The cellular and molecular defense mechanisms of
the Candida yeasts against azole antifungal drugs, Journal de
Mycologie Medicale, vol. 22, pp. 173178, 2012.
[96] R. D. Cannon, E. Lamping, A. R. Holmes et al., Efflux-mediated
antifungal drug resistance, Clinical Microbiology Reviews, vol.
22, no. 2, pp. 291321, 2009.
[97] A. T. Coste, M. Karababa, F. Ischer, J. Bille, and D. Sanglard,
TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans
ABC transporters CDR1 and CDR2, Eukaryotic Cell, vol. 3, no.
6, pp. 16391652, 2004.
[98] A. Coste, V. Turner, F. Ischer et al., A mutation in TAC1p, a
transcription factor regulating CDR1 and CDR2, is coupled with
loss of heterozygosity at chromosome 5 to mediate antifungal
resistance in Candida albicans, Genetics, vol. 172, no. 4, pp.
21392156, 2006.
[99] A. T. Coste, J. Crittin, C. Bauser, B. Rohde, and D. Sanglard,
Functional analysis of cis-and trans-acting elements of the
Candida albicans CDR2promoter with a novel promoter
reporter system, Eukaryotic Cell, vol. 8, no. 8, pp. 12501267,
2009.
[100] R. Torelli, B. Posteraro, S. Ferrari et al., The ATP-binding
cassette transporter-encoding gene CgSNQ2 is contributing to
the CgPDR1-dependent azole resistance of Candida glabrata,
Molecular Microbiology, vol. 68, no. 1, pp. 186201, 2008.
[101] D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and
J. Bille, The ATP binding cassette transporter gene CgCDR1
from Candida glabrata is involved in the resistance of clinical
isolates to azole antifungal agents, Antimicrobial Agents and
Chemotherapy, vol. 43, no. 11, pp. 27532765, 1999.
[102] J. E. Bennett, K. Izumikawa, and K. A. Marr, Mechanism of
Increased Fluconazole Resistance in Candida glabrata during
Prophylaxis, Antimicrobial Agents and Chemotherapy, vol. 48,
no. 5, pp. 17731777, 2004.
[103] G. P. Moran, D. Sanglard, S. M. Donnelly, D. B. Shanley, D. J.
Sullivan, and D. C. Coleman, Identification and expression of
multidrug transporters responsible for fluconazole resistance in
Candida dubliniensis, Antimicrobial Agents and Chemotherapy,
vol. 42, no. 7, pp. 18191830, 1998.
[104] E. Lamping, A. Ranchod, K. Nakamura et al., Abc1p is a
multidrug efflux transporter that tips the balance in favor of
innate azole resistance in Candida krusei, Antimicrobial Agents
and Chemotherapy, vol. 53, no. 2, pp. 354369, 2009.
[105] S. K. Katiyar and T. D. Edlind, Identification and expression of
multidrug resistance-related ABC transporter genes in Candida
krusei, Medical Mycology, vol. 39, no. 1, pp. 109116, 2001.
[106] J.-P. Vermitsky and T. D. Edlind, Azole resistance in Candida
glabrata: coordinate upregulation of multidrug transporters
and evidence for a Pdr1-like transcription factor, Antimicrobial
Agents and Chemotherapy, vol. 48, no. 10, pp. 37733781, 2004.
[107] J.-P. Vermitsky, K. D. Earhart, W. L. Smith, R. Homayouni, T. D.
Edlind, and P. D. Rogers, Pdr1 regulates multidrug resistance in
Candida glabrata: gene disruption and genome-wide expression
studies, Molecular Microbiology, vol. 61, no. 3, pp. 704722,
2006.
[108] H.-F. Tsai, A. A. Krol, K. E. Sarti, and J. E. Bennett, Candida
glabrata PDR1 , a transcriptional regulator of a pleiotropic drug
resistance network, mediates azole resistance in clinical isolates
and petite mutants, Antimicrobial Agents and Chemotherapy,
vol. 50, no. 4, pp. 13841392, 2006.
[109] C. M. Martel, J. E. Parker, O. Bader et al., Identification and
characterization of four azole-resistant erg3 mutants of Candida
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
[129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
13
[139] A. A. L. Gunatilaka, Natural products from plant-associated
microorganisms: distribution, structural diversity, bioactivity,
and implications of their occurrence, Journal of Natural Products, vol. 69, no. 3, pp. 509526, 2006.
[140] N. G. Aher, V. S. Pore, N. N. Mishra et al., Synthesis and
antifungal activity of 1,2,3-triazole containing fluconazole analogues, Bioorganic and Medicinal Chemistry Letters, vol. 19, no.
3, pp. 759763, 2009.
[141] G. Kofla and M. Ruhnke, Pharmacology and metabolism of
anidulafungin, caspofungin and micafungin in the treatment of
invasive candidosisreview of the literature, European Journal
of Medical Research, vol. 16, no. 4, pp. 159166, 2011.
[142] A. Fernandez, E. Soriano, P. Hernandez-Munoz, and R. Gavara,
Migration of antimicrobial silver from composites of polylactide with silver zeolites, Journal of Food Science, vol. 75, no. 3,
pp. E186E193, 2010.
[143] O. Ozay, A. Akcali, M. T. Otkun, C. Silan, N. Aktas, and N.
Sahiner, P(4-VP) based nanoparticles and composites with
dual action as antimicrobial materials, Colloids and Surfaces B,
vol. 79, no. 2, pp. 460466, 2010.
[144] N.-A. Watanabe, M. Miyazaki, T. Horii, K. Sagane, K. Tsukahara, and K. Hata, E1210, a new broad-spectrum antifungal,
suppresses Candida albicans hyphal growth through inhibition of glycosylphosphatidylinositol biosynthesis, Antimicrobial Agents and Chemotherapy, vol. 56, no. 2, pp. 960971, 2012.
[145] M. Miyazaki, T. Horii, K. Hata et al., In vitro activity of E1210, a
novel antifungal, against clinically important yeasts and molds,
Antimicrobial Agents and Chemotherapy, vol. 55, no. 10, pp.
46524658, 2011.
[146] J. Bartroli and M. Merlos, Overview of albaconazole, European
Infectious Disease, vol. 5, no. 2, pp. 8891, 2011.
[147] J. Majithiya, A. Sharp, A. Parmar, D. W. Denning, and P. A.
Warn, Efficacy of isavuconazole, voriconazole and fluconazole
in temporarily neutropenic murine models of disseminated
Candida tropicalis and Candida krusei, Journal of Antimicrobial
Chemotherapy, vol. 63, no. 1, pp. 161166, 2009.
[148] F. C. Odds, Drug evaluation: BAL-8557a novel broadspectrum triazole antifungal, Current Opinion in Investigational Drugs, vol. 7, no. 8, pp. 766772, 2006.
[149] J. Livermore and W. Hope, Evaluation of the pharmacokinetics
and clinical utility of isavuconazole for treatment of invasive
fungal infections, Expert Opinion on Drug Metabolism &
Toxicology, vol. 8, pp. 759765, 2012.